RESEARCH ARTICLE Kina Ho¨glund Æ Steinar Syversen Æ Piotr Lewczuk Anders Wallin Æ Jens Wiltfang Æ Kaj Blennow Statin treatment and a disease-specific pattern of b-amyloid peptides in Alzheimer’s disease Received: 23 August 2004 / Accepted: 16 November 2004 / Published online: 4 June 2005 Ó Springer-Verlag 2005 Abstract According to the amyloid cascade hypothesis, sporadic Alzheimer’s disease (AD) is caused by the production and aggregation of b-amyloid (Ab), and the production of Ab has recently been linked to the metabolism of cholesterol. We have previously pub- lished clinical studies where the effect of statin treatment on Ab production has been investigated. No effect on Ab was found, which is in disagreement with cell and animal studies. In the present study we investigated the effect of statin treatment on a disease-specific pattern consisting of a C-terminally-truncated quintet of Ab peptides. Nineteen patients with AD were treated with simvastatin for 12 months and the quintet of Ab pep- tides were analysed in cerebrospinal fluid before and after treatment. Also included was a group of 15 un- treated patients with AD. We found that the Ab peptide pattern at baseline was in agreement with earlier find- ings; however, we did not find any change in the Ab peptide pattern after statin treatment. We suggest that clinical studies with extended treatment periods are performed where higher dosages of statins are used. We also believe that the pleiotropic effects of statins should be investigated further in order to elucidate the con- nection between Alzheimer’s disease and statin treat- ment. Keywords Alzheimer’s disease Æ Ab Æ Ab peptide pattern Æ APP Æ Cholesterol Æ Statins Introduction The processing of amyloid precursor protein (APP) re- sults in the production of b-amyloid (Ab) peptide, a major constituent of senile plaques (SP), a pathological hallmark in Alzheimer’s disease (AD). According to the amyloid cascade hypothesis, the production and aggre- gation of Ab peptides are central events in the aetiology of sporadic AD. Evidence for this hypothesis comes from several lines of inquiry: (1) the disease-causing mutations found in APP, Presenilin 1 (PS1) and Prese- nilin 2 (PS2) genes all lead to an upregulation of Ab40 and/or Ab42 peptides (Scheuner et al 1996); (2) indi- viduals with trisomy 21 (with three APP genes) develop AD pathology in their fourth or fifth decade of life (Wisniewski et al 1985; Iwatsubo et al 1995); (3) allelic variation of the apolipoprotein E (ApoE) gene is a risk factor for sporadic AD, and since ApoE binds to Ab (Strittmatter et al 1993a, 1993b), it may be involved in the formation of SP. APP is ubiquitously expressed in all cells and is se- creted by both brain and peripheral cells into extracel- lular fluids. The initial cleavage of APP is made by either a- or b-secretase, producing the soluble fragments asAPP or bsAPP and the corresponding C-terminal fragment C83 or C99 (Andreasen and Blennow 2002). The C-ter- minal fragments remain membrane-bound and are sub- strates for the subsequent intramembranous cleavage by the c-secretase complex, producing p3 or Ab (Andreasen and Blennow 2002). The cleavage by a-secretase occurs after Lys16 within the Ab sequence, thereby precluding the formation of Ab. The identity of a-secretase is still not clear, but three candidates have been suggested: tu- mour necrosis factor-a-converting enzyme (TACE), also called ADAM17, ADAM10 (a disintegrin and metallo- protease) and MDC9 (metallo/disintegrin/cystein-rich K. Ho¨glund (&) Æ K. Blennow Institute of Clinical Neuroscience, Section of Experimental Neurochemistry, Go¨teborg University, Neurolabb, SU/Mo¨lndal, 43180 Mo¨lndal, Sweden E-mail: kina.hoglund@neuro.gu.se Tel.: +46-31-3432377 Fax: +46-31-3432426 S. Syversen Æ A. Wallin Institute of Clinical Neuroscience, Section of Psychiatry, Go¨teborg University, Sweden P. Lewczuk Æ J. Wiltfang Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany Exp Brain Res (2005) 164: 205–214 DOI 10.1007/s00221-005-2243-8